Mental Retardation, X-Linked 104

A number sign (#) is used with this entry because of evidence that X-linked mental retardation-104 (MRX104) is caused by mutation in the FRMPD4 gene (300838) on chromosome Xp22.

Clinical Features

Hu et al. (2016) reported a large family (P58) in which 5 males had mild to severe intellectual disability with variable seizures, poor or absent speech, and behavioral problems. They also reported an unrelated patient (L87) who presented at age 17 years with significant developmental delay, absence of speech, and autism spectrum disorder.

Piard et al. (2018) reported follow-up of the patients reported by Hu et al. (2016) and identified 4 additional male patients from 2 additional unrelated families. Including the previous report, there were 10 affected males from 4 unrelated families with patients ranging from 4 to 66 years of age. All patients had global developmental delay with variably impaired intellectual development. Acquisition of walking was mildly delayed (by 30 months at the latest), and speech was also delayed, although several patients were unable to speak in their teens. Some patients had behavioral abnormalities, including autism spectrum disorder, hyperactivity, and aggression. Less common neurologic findings included hypotonia, spasticity, hyperreflexia, ataxia, and tremor. Two brothers had ophthalmic findings, including strabismus, nystagmus, myopia, and optic atrophy with no eye contact (in 1 of them), and another unrelated boy had strabismus and no eye contact. One patient in the large previously reported family had onset of seizures at age 19 years, whereas 2 sibs in another family had onset of focal seizures in the first years of life. Brain imaging, performed in a few patients, showed nonspecific and variable abnormalities, such as thin corpus callosum, cortical atrophy, and delayed myelination. A few patients had dysmorphic features, such as high forehead, retrognathia, dysplastic ears, frontal hair upsweep, broad nasal bridge, high-arched palate, and mild hand anomalies, but there was no distinctive facial gestalt. In 1 family, a female mutation carrier was noted to be mildly affected.

Inheritance

The transmission pattern of MRX104 in the family reported by Hu et al. (2016) was consistent with X-linked recessive inheritance.

Molecular Genetics

In 5 affected males from a family (P58) with MRX104, Hu et al. (2016) identified a hemizygous truncating mutation in the FRMPD4 gene (300838.0001). An unrelated male patient (L87) with MRX104 was found to carry a de novo hemizygous missense mutation in the FRMPD4 gene (R415W; 300838.0002). The mutations were found by X-chromosome exome sequencing of 405 probands with X-linked intellectual disability. Functional studies of the variants were not performed.

In affected members of 2 unrelated families with MRX104, Piard et al. (2018) identified hemizygous mutations in the FRMPD4 gene (300838.0003 and 300838.0004). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Including the previous report (Hu et al., 2016), there was 1 frameshift mutation, 1 nonsense mutation, 1 deletion of a coding exon, and 1 missense mutation. Piard et al. (2018) noted that the frameshift mutation previously reported by Hu et al. (2016) (300838.0001) predicts a truncated protein that lacks the C-terminal HOMER binding domain and the PDZ binding domain. In vitro functional expression studies in HEK293 cells showed that the mutation disrupted FRMPD4 binding with PSD95 and HOMER1. When transfected into rat hippocampal cells, the mutated protein failed to increase spine density and caused abnormal spine morphology, consistent with a loss of function. Functional studies of the other variants and studies of patient cells were not performed. The authors speculated that FRMPD4 mutations likely also disrupt the proper assembly of the FRMPD4 protein complex that regulates certain glutamate receptors. Both mechanisms may contribute to cognitive dysfunction via a loss-of-function effect.

Animal Model

Piard et al. (2018) found that Frmpd4-null mice demonstrated deficits in hippocampal-based spatial learning and memory compared to controls.